Addiction to psychostimulants such as cocaine is a serious health problem that involves neurobiological changes in limbic and cortical circuits that engage cognitive and emotive processing. Until recently, most work has focused on understanding the reward processes mediated by limbic circuits, particularly the reinforcing effects of cocaine that result from increased dopamine (DA) activity due to blockade of the presynaptic DA transporter. However, the cellular adaptations that underlie unmanageable drug seeking and reduced motivation for natural reward are not as well understood. Results from recent neuroimaging studies in humans and animals have implicated additional brain areas, particularly the prefrontal cortex (PFC). Several recent studies have suggested potential mechanisms that could account for such a purported hypoactive frontal cortex: Our own intracellular recordings in-vivo show that both acute and repeated administration of cocaine disrupts the normal membrane transitions between quiet down-states and depolarized up-states during which spike firing occurs. It has been shown that DA innervation from the VTA and GABAergic interneurons in the PFC help tune the recurrent excitation in PFC networks that may ultimately underlie cognition. Alterations in dopaminergic transmission resulting from repeated treatment with cocaine could therefore induce aberrant firing patterns in interneurons and pyramidal cells, thus altering the integration of diverse information in the cortex. This proposal outlines electrophysiological experiments to study the enduring neuroadaptations induced in PFC interneurons by repeated administration of cocaine. This work is significant because the effects of repeated cocaine treatment on cortical interneurons and the consequences of altering GABAergic inhibition in the PFC have not been studied. Whole-cell clamp recordings in vitro and intracellular and extracellular recordings in vivo will be made from pyramidal cells and interneurons in the PFC of rats that have been treated repeatedly with cocaine. The overarching hypothesis of this proposal is that repeated cocaine administration produces increases in the activity of cortical GABA interneurons.Narrative: Addiction to psychostimulants such as cocaine is a serious health problem that involves neurobiological changes in limbic and cortical circuits that engage cognitive and emotive processing. This porposal will evaluate potential new cellular targets for a more directed therapeutical approach that hopefully could target the cognitive and emotive processes disturbed by the repeated use of psychostimulants. [unreadable] [unreadable] [unreadable]